We plan to study the neurochemical basis for long-lasting sensitization to the stimulant effects of morphine, d-amphetamine, cocaine and methylphenidate. In order to establish the genetic determinants for the responses to these drugs we will use recombinant-inbred lines of mice. Several regions of the brain will be examined for the concentration and turnover rate of dopamine and norepinephrine. We will look for pharmacologic and neurochemical evidence of dopaminergic supersensitivity in sensitized mice. We will also measure narcotic receptors and eukephalin levels in the brains of strains of mice that differ in their analgesic response to morphine. The rate of metabolism of d-amphetamine in the livers of different strains of mice will be measured and correlated with genetic differences in response. The results of these experiments may help to explain why individual patients and addicts vary in their responses to narcotic and stimulant drugs. This work may also give some insight into long-lasting changes in drug sensitivity that persist after withdrawal.